1. Field of the Invention
The present invention relates to pharmaceutical compositions and methods for increasing neurotrophic peptides related to the antagonism of sortilin.
2. Description of Related Art
Sortilin (see FIG. 1) is a toroid protein that is involved in the trafficking of other proteins, notably neurotensin, amyloid-beta precursor protein, and progranulin (PRGN). In the case of progranulin, sortilin is one of the primary receptors, the other being tumor necrosis factor receptor (TNFR). In the neurons, PRGN is removed by sortilin-mediated endocytosis. Brain PRGN is known to be haploinsufficient (about 50% of normal) in patients with frontotemporal dementia (FTD). This condition causes degeneration of the frontal lobe of the brain, and is progressive with age. FTD is associated with behavioral changes, speech and language problems, and in rarer cases motor disorders that resemble Parkinsonism. Without being bound to a particular theory, it is believed that FTD is due primarily to deletions or mutations in the PRGN gene. Mutations in the PRGN gene, e.g., have been identified as a major cause of frontotemporal lobar disease, with ubiquitin-positive inclusions (FTLD-U). There is currently no effective pharmacological treatment for FTD.
Another protein, the survival motor neuron (SMN) protein that is found in cortical neurons, is known to be present at levels far below normal in patients with spinal muscular atrophy (SMA). This disorder, in which neural support of muscle integrity is lacking, is fairly common and is fatal in infants. SMA also occurs in older patients. It is a neuromuscular disease characterized by the specific degeneration of SMN protein. Without being bound to a particular theory, it is believed that this is due primarily to deletions or mutations in the SMN1 gene. Currently there is no effective treatment for this disorder. Other diseases and disorders characterized by loss or reduction of SMN protein include motor neuron diseases such as amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease.
Thus, the need exists for effective pharmacological and pharmaceutical compositions and methods for increasing the level of defined neurotrophic proteins in humans, and for treating, preventing, inhibiting, or reversing neurodegenerative diseases or conditions in a subject in need thereof wherein the disease or condition is mediated at least in part by the level of said defined neural proteins.